title: Loss of Apelin exacerbates myocardial infarction adverse remodeling and ischemia-reperfusion injury: therapeutic potential of synthetic Apelin analogues.
abstract: BACKGROUND
  Coronary artery disease leading to myocardial ischemia is the most common cause of heart failure. Apelin (APLN), the endogenous peptide ligand of the APJ receptor, has emerged as a novel regulator of the cardiovascular system.
  
  
  RESULTS
  Here we show a critical role of APLN in myocardial infarction (MI) and ischemia-reperfusion (IR) injury in patients and animal models. Myocardial APLN levels were reduced in patients with ischemic heart failure. Loss of APLN increased MI-related mortality, infarct size, and inflammation with drastic reductions in prosurvival pathways resulting in greater systolic dysfunction and heart failure. APLN deficiency decreased vascular sprouting, impaired sprouting of human endothelial progenitor cells, and compromised in vivo myocardial angiogenesis. Lack of APLN enhanced susceptibility to ischemic injury and compromised functional recovery following ex vivo and in vivo IR injury. We designed and synthesized two novel APLN analogues resistant to angiotensin converting enzyme 2 cleavage and identified one analogue, which mimicked the function of APLN, to be markedly protective against ex vivo and in vivo myocardial IR injury linked to greater activation of survival pathways and promotion of angiogenesis.
  
  
  CONCLUSIONS
  APLN is a critical regulator of the myocardial response to infarction and ischemia and pharmacologically targeting this pathway is feasible and represents a new class of potential therapeutic agents.
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.forename: Shaun M K
authors.initials: SM
authors.lastname: McKinnie
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.forename: George
authors.initials: G
authors.lastname: Haddad
authors.forename: Zuocheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Pavel
authors.initials: P
authors.lastname: Zhabyeyev
authors.forename: Subhash K
authors.initials: SK
authors.lastname: Das
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.forename: Brent
authors.initials: B
authors.lastname: McLean
authors.forename: Vijay
authors.initials: V
authors.lastname: Kandalam
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: John C
authors.initials: JC
authors.lastname: Vederas
authors.forename: Allan G
authors.initials: AG
authors.lastname: Murray
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D054392:Adipokines; D000818:Animals; D000073861:Apelin; D002317:Cardiovascular Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D010455:Peptides / Q000494:pharmacology; D020127:Recovery of Function; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: C115436:APLN protein, human; D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; D002317:Cardiovascular Agents; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides
keywords: angiogenesis; cardiomyopathy; heart failure; ischemia‐reperfusion injury; myocardial infarction